This invention concerns certain 3-substituted-2,5-morpholinediones and their polymerization or copolymerization to bioabsorbable depsipeptide polymers which can be fabricated into useful medical implant devices such as sutures.
For the past decade or so, synthetic resorbable sutures have been replacing natural catgut in many applications as biodegradable wound closures since the synthetics, unlike the natural polymers, are consistent and predictable in their strength and sorption properties.
At present, the synthetic suture market is dominated by high molecular weight polyglycolic acid (PGA) and a modified PGA copolymer containing about 10 mole percent lactic acid. Despite their superiority to catgut, however, these resins lack certain desirable properties. For example, they tend to be resorbed too readily, they are too rigid as monofilaments, and they cannot be sterilized by irradiation.
Certain modifications of these resins have been introduced in an attempt to overcome such limitations. For example, U.S. Pat. No. 4,052,988 discloses a poly(p-dioxanone) (PDS) having a structure similar to PGA but purportedly of a lower resorption rate and more readily handled as monofilaments. Such property improvements are also claimed by the modified PGA polymers of U.S. Pat. Nos. 4,209,607 and 4,343,931, which incorporate amide bonding into the polymer chain.
Attempts at preparing resorbable polydepsipeptides include the copolymerization of a racemic N-carboxyanhydride with a racemic anhydrosulfite as disclosed in U.S. Pat. No. 3,773,737. Such a copolymerization, however, produces a heterogeneous product having random and racemic ester/amide groups and is therefore incapable of yielding crystalline polymers. The copolymerization of p-dioxanone with up to 15 mole percent of a 2,5-morpholinedione disclosed in U.S. Pat. No. 4,441,496 was purported to improve the resorption rate of PDS. Recent publications by Helder et al., Makromol. Chem., Rapid Commun., 6, 9-14, 1985, and Yonezawa et al., ibid, 6, 607-611, 1985, have demonstrated the preparation of polydepsipeptides from the ring-opening polymerization of 6-substituted-2,5-morpholinediones.
Despite such developments, the need still exists for a true alternating bioabsorbable polymer of suitable strength and resorption rate which can be readily melt processed. The primary objective of the present invention, therefore, is to satisfy this need.
Preparation of 3-benzyl-2,5-morpholinediones, employed in this invention, by silver oxide catalyzed condensation of N-(bromoacetyl)-L-phenylalanine is reported by Rumsh et al., FEBS Letters, 9, 64, 1970.